CA2219202A1 - Apparatus and method for sterilizing, seeding, culturing, storing, shipping and testing tissue, synthetic or native vascular grafts - Google Patents
Apparatus and method for sterilizing, seeding, culturing, storing, shipping and testing tissue, synthetic or native vascular grafts Download PDFInfo
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- CA2219202A1 CA2219202A1 CA002219202A CA2219202A CA2219202A1 CA 2219202 A1 CA2219202 A1 CA 2219202A1 CA 002219202 A CA002219202 A CA 002219202A CA 2219202 A CA2219202 A CA 2219202A CA 2219202 A1 CA2219202 A1 CA 2219202A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
- A61F2/06—Blood vessels
- A61F2/062—Apparatus for the production of blood vessels made from natural tissue or with layers of living cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/24—Apparatus using programmed or automatic operation
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M21/00—Bioreactors or fermenters specially adapted for specific uses
- C12M21/08—Bioreactors or fermenters specially adapted for specific uses for producing artificial tissue or for ex-vivo cultivation of tissue
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M23/00—Constructional details, e.g. recesses, hinges
- C12M23/02—Form or structure of the vessel
- C12M23/06—Tubular
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M25/00—Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
- C12M25/14—Scaffolds; Matrices
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M35/00—Means for application of stress for stimulating the growth of microorganisms or the generation of fermentation or metabolic products; Means for electroporation or cell fusion
- C12M35/04—Mechanical means, e.g. sonic waves, stretching forces, pressure or shear stimuli
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Sustainable Development (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Vascular Medicine (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Epidemiology (AREA)
- Clinical Laboratory Science (AREA)
- Transplantation (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Mechanical Engineering (AREA)
- Cell Biology (AREA)
- Molecular Biology (AREA)
- Pulmonology (AREA)
- Cardiology (AREA)
- Dermatology (AREA)
- Medicinal Chemistry (AREA)
- Apparatus Associated With Microorganisms And Enzymes (AREA)
- Prostheses (AREA)
- Materials For Medical Uses (AREA)
- Pretreatment Of Seeds And Plants (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
An apparatus and method for sterilizing, seeding, culturing, storing, shipping, and testing vascular grafts is disclosed. Specifically, the present invention relates to an apparatus and method for seeding and culturing vascular grafts with human cells. The apparatus includes a fluid reservoir (10), a pump (12), an alternating pressure source (16), and at least one treatment chamber (14). By alternating pressure to a support structure (32) within the treatment chamber (14) upon which a vascular graft scaffold (26) is positioned, a varying radial stress is placed on the scaffold (26). This stress results in a tissue-engineered vascular graft with cells and their fibers oriented in a manner which is more likely to possess long term dimensional stability and the patency of native vessels with normal physiologic function.
Description
W096/34~90 PCT~S96105151 APPARATUS ~ND M~THOD FOR STERI~IZING, SEEDING, CULTURINGJ
STORING, SHIPPING AND TESTING TISSUE, ~YNln~llC OR
NATIVE VASCULAR GRAFTS
BACKGROUn~D OF THE lNv~:~LloN
Technical Field lD The present invention relates to the sterilization, seeding, culturing, storing, shipping, and testing of vascular grafts. Specifically, the present invention relates to an apparatus and method for sterilizing vascular gra~ts and then seeding and culturing the grafts with human cells, 15 resulting in grafts populated with viable human cells.
Di~cu~;sion o~ the Related Art Vascular grafts are used by vascular and thoracic surgeons to repair or replace segments of arterial and venous 20 blood vessels that are weakened, damaged, or obstructed due to trauma or disease such as aneurysm, atherosclerosis, and diabetes mellitus. Historically, vascular grafts have been either homografts, such as the patient's own saphenous vein or internal m~mm~ry artery, prosthetic grafts made of
STORING, SHIPPING AND TESTING TISSUE, ~YNln~llC OR
NATIVE VASCULAR GRAFTS
BACKGROUn~D OF THE lNv~:~LloN
Technical Field lD The present invention relates to the sterilization, seeding, culturing, storing, shipping, and testing of vascular grafts. Specifically, the present invention relates to an apparatus and method for sterilizing vascular gra~ts and then seeding and culturing the grafts with human cells, 15 resulting in grafts populated with viable human cells.
Di~cu~;sion o~ the Related Art Vascular grafts are used by vascular and thoracic surgeons to repair or replace segments of arterial and venous 20 blood vessels that are weakened, damaged, or obstructed due to trauma or disease such as aneurysm, atherosclerosis, and diabetes mellitus. Historically, vascular grafts have been either homografts, such as the patient's own saphenous vein or internal m~mm~ry artery, prosthetic grafts made of
2~ synthetic materials such as polyester (e.g., Dacron), expanded polytetraflouroethylene (ePTFE), and other composite materials, or fresh or fixed biological tissue grafts.
However, synthetic grafts generally have inadequate patency rates for many uses, while the harvesting of 30 homografts requires extensive surgery which is time-consuming, costly, and traumatic to the patient. Fixed tissue grafts do not allow for infiltration and colonization by the host cells, which is essential to remodeling and tissue maintenance. Consequently, fixed tissue grafts
However, synthetic grafts generally have inadequate patency rates for many uses, while the harvesting of 30 homografts requires extensive surgery which is time-consuming, costly, and traumatic to the patient. Fixed tissue grafts do not allow for infiltration and colonization by the host cells, which is essential to remodeling and tissue maintenance. Consequently, fixed tissue grafts
3~ degrade with time and will eventually malfunction.
Due to the inadequacies of these currently available synthetic and biological grafts, as well as the cost and CA 022l9202 l997-l0-27 PCTnUS96/05151 limited supply of homografts, tissue engineered grafts are being developed which have been sterilized and then seeded and cultured, in vitro, with cells. These tissue engineered grafts may be superior to other grafts for use in replacement 5 therapy in that they more closely display the long term dimensional stability and patency of native arteries and vessels with normal physiologic functionality.
Historically, the seeding and culturing of vascular grafts, and tissue in general, has taken place in a static 10 environment such as a Petri or culture dish. However, there are disadvantages to seeding and culturing tissue in such an environment. For example, the lack of circulation of nutrients in these static systems results in a slow and ineffective seeding and culturing process. Moreover, cells 1~ which are seeded and cultured in a dynamic environment are more likely to tolerate the physiological conditions which exist in the human body once implanted. Thus, there exists a need for a dynamic environment in which to seed and culture tissue-engineered vascular grafts and other prosthetic 20 devices.
SUk~ARY OF THE lNv~:N-lloN
It is therefore an object of the invention to provide a dynamic environment for seeding, culturing, and testing 25 vascular grafts of any desired length or diameter.
It is a further object of the invention to provide a precise mechanical device with a minimum of moving parts to provide such an environment.
It is yet a further object of the invention to provide a 30 closed system free from contamination for sterilizing, seeding, culturing, storing, shipping, and testing vascular grafts.
In accordance with the present invention, there is provided an apparatus and method for sterilizing, seeding, 35 culturing, storing, shipping, and testing vascular grafts.
Specifically, the present invention is an apparatus and method for seeding and culturing vascular grafts with human .
, PCTnUS96J051~1 WO g6~34090 cells, resulting in a tissue-engineered vascular graft populated with viable human cells.
The apparatus according to the invention comprises a fluid reservoir, a pump, at least one gra~t treatment 5 chamber, a tube for supporting the graft in the treatment chamber, and an alternating pressure source for applying a radial stress to the prosthesis housed in the treatment chamber. Applying radial stress to the vascular graft scaffold located on the tube within the treatment chamber lO during seeding and culturing results in a vascular graft with cells and their fibers oriented so as to more likely tolerate the physiological conditions found in the human body. In this manner, the invention advantageously utilizes a mechanically non-complex apparatus to create a dynamic 15 environment in which to seed and culture tissue-engineered vascular grafts or other implantable devices.
BRIEF DESCRIPTION OF THE DRAWINGS
These and other features, aspects, and advantages of the 20 present invention will become more readily apparent from the following detailed description, which should be read in conjunction with the accompanying drawings in which:
FIG. 1 is a schematic diagram illustrating an apparatus according to the present invention for sterilizing, seeding, 25 culturing, storing, shipping, and testing a prosthesis;
FIG. 2 is a block diagram illustrating a preferred embodiment of an alternating pressure source;
FIG. 3 is a schematic diagram illustrating an alternative exemplary embodiment of the present invention for 30 sterilizing, seeding, culturing, storing, shipping, and testing a prosthesis, in which a plurality of prostheses may be treated simultaneously; and FIG. 4 is a schematic diagram illustrating yet another alternative exemplary embodiment of an apparatus according to 35 the present invention for sterilizing, seeding, culturing, storing, shipping, and testing a prosthesis.
CA 02219202 1997-10-27 PCT~US96/05151 DET~TT~n DESCRIPTION OF THE lNV~N-llON
The following embodiments of the present invention will be described in the context of an apparatus and method for sterilizing, seeding, culturing, storing, shipping, and 5 testing vascular grafts, although those skilled in the art will recognize that the disclosed methods and structures are readily adaptable for broader application. Note that whenever the same reference numeral is repeated with respect to different figures, it refers to the corresponding 10 structure in each such figure.
FIG. 1 discloses a system for sterilizing, seeding, culturing, storing, shipping, and testing vascular grafts.
According to a preferred embodiment of the invention, this system primarily comprises a fluid reservoir 10, a pump 12, a 15 treatment chamber 14, and an alternating pressure source 16.
Fluid reservoir 10 is used to store fluid for the system. Two illustrative suitable reservoirs are the Gibco-BRL lL media bag and any rigid container capable of sterilization. Reservoir 10 may include a one way filter so 20 as to provide a direct source of gas to the fluid within the system. Examples of fluid which may be used in the system include, but are not limited to, sterilizing fluid, t~nn; ng fluid, fluid containing cells, or fluid containing a culture medium. It is to be understood that during testing, seeding, 25 and culturing in a preferred embodiment, the fluid may be advantageously kept at human body temperature, and may be composed of a fluid which approximates the viscosity of human blood. One illustrative example of a solution which approximates the viscosity of blood is saline with glycerol.
The fluid contained in reservoir 10 is retrieved through fluid line 18 by pump 12. Fluid line 18, as well as all other fluid lines in the system, may be made of any type of medical grade, durable tubing suitable for transporting the fluid in use. Pump 12 may be preferably any fluid pump which 35 can achieve variable ~low rates. One such pump is the Masterflex L/S Digital Drive peristaltic pump manufactured by Cole-Palmer, although one skilled in the art could select PC~nUS961~5~5 WO 96/340gO
from a variety of commercially available pumps. Pump 12 propels the fluid from reservoir 10 to treatment chamber 14 through fluid line 20.
Treatment chamber 14 preferably may be composed of any 5 biocompatible, rigid material capable of being sterilized such as Teflon, polycarbonate, PVC, or stainless steel.
Treatment chamber 14 may be comprised of two sections which are secured and made leak proof through any standard means such as inner and ou~er threads or the use of bonding agents.
10 In order to view vascular grafts within treatment chamber 14, a viewing port may be placed at any point on the chamber, or alternatively, the chamber may be made of an optically clear material such as polycarbonate or PVC. Inlet port 28 and outlet port 30 of ~reatment chamber 14 allow for the 1~ perfusion and/or circulation of fluid into and through the chamber. Inlet port 28 and outlet port 30 are also used to attach treatment chamber 14 to fluid lines 20 and 22 respectively. Fluid line 22 connects chamber 14 back to fluid reservoir 10 so as to create a closed system.
Treatment chamber 14 houses an expandable tube 32 upon which may be placed a vascular graft scaffolding 26. As is discussed in detail in both the patents incorporated by reference below, scaffolding 26 may illustratively consist of any knitted, braided, woven, felted, or synthesized materials 2~ that are bioresorbable and/or biocompatible, as well as any native graft scaffolding material. Tube 32 may be comprised of any suitable elastomeric material, such as PET or silicone angioplasty balloons, which is capable of expanding and contracting. Treatment Chamber 14 and tube 32 may be made 30 any length or diameter so as to hold a vascular graft scaffolding 26 of any length or diameter. This is advantageous, as the system may be used to sterilize, seed, culture, store, ship, and test vascular grafts of any size, ~uch as coronary, carotid, iliac, and peripheral leg grafts.
35 A porous clip or grommet 33 may be placed on tube 32 at both ends of scaffolding 26 to hold the scaffolding firmly in = place on the tube during treatment. However, one skilled in 096/34090 PCTrUS96/05151 the art will understand that any structure which allows for retention of the scaffolding 26 on tube 32 may be used.
Grommets 33 are beneficial, as the tubing can be made smaller than the grafts so as to allow for the perfusion and/or circulation of fluids in between the graft and the tube, without the possibility of slippage of the graft on the tube.
Tube 32 may be expanded and contracted by alternating pressure source 16, a preferred embodiment of which is shown in detail in FIG. 2. Specifically, FIG. 2 shows a pump 34 which may be any standard pump capable of providing both positive pressure and negative (or vacuum) pressure, such as a piston or diaphragm pump. Valve 36 accepts the positive pressure and negative pressure from pump 34 through lines 40 and 42 respectively. Due to signal& from timer 38, valve 36 causes alternating pressure to be applied to tube 32 from line 24. Valve 36 may be any type of inline valve capable of directing and regulating multiple pressure lines. One such valve is the MAC 45S, model 45A-AA1-DAAA-lBA.
By expanding and contracting tube 32 with alternating pressure source 16, tube 32 places a varying radial stress on vascular graft scaffolding 26. This radial stress is advantageous as it can be detected by living cells attached to the scaffolding, thus causing the cells to align themselves parallel to the axis of stress and to secrete extracellular matrix molecules which are also aligned parallel to the axis of stress. In this manner, vascular grafts are formed with cells and their fibers configured so as to more likely tolerate the physiological conditions found in the human body.
The system according to the present invention may contain a plurality of chambers 14 for treating a plurality of vascular grafts. FIG. 3 discloses a system according to the present invention which contains two treatment chambers 14. Although FIG. 3 illustrates the connection of only two treatment chambers to the system, it will be apparent to one skilled in the art that any number of chambers may be connected to the system in similar fashion. Specifically, WO 96/34090 PCTnUS96105151 line 20 may be split to connect to each inlet 28, line 24 may be split to connect to each tube 32, and line 22 may be split to connect to each outlet 30 of each chamber 14 in the system. In this manner, a plurality of vascular grafts may 5 be simultaneously seeded, cultured, or tested.
Alternatively, each treatment chamber 14 may be connected to a separate reservoir 10 and pump 12 so that multiple treatment chambers in a system would only share a single alternating pressure source 16. It is to be 10 understood that a pump 12 with multiple pump lines may also be used so that each treatment chamber 14 in the system would use the same alternating pressure source and same pump 12 (each using a different pump line), but would be connected to a different media reservoir 10.
FIG. 4 discloses an alternative embodiment of the invention for sterilizing, seeding, culturing, storing, shipping, and testing vascular grafts. According to this - embodiment of the invention, the system primarily comprises a fluid reservoir 10, a bladder pump S0, a treatment chamber 20 46, and an alternating pressure source 54.
Fluid reservoir 10 and the fluids which it may contain are described in detail in conjunction with FIG. 1. The fluid contained in reservoir 10 is retrieved through fluid line 60 by bladder pump 50. Fluid line 60, as well as all 25 other fluid lines in the system, may be made of any type of medical grade, durable tubing suitable for transporting the fluid in use. Bladder pump 50 is comprised of a pneumatic pressure chamber 51 and a bladder 53, which may be comprised of an suitable elastomeric material. An illustrative 30 suitable bladder is the Cutter/Miles double valved hand activated blood pump. Bladder pump 50 forces fluid from reservoir 10 to treatment chamber 46 through fluid line 58 by being alternately compressed and expanded by alternating - pressure source 54 in conjunction with valve 52 and timer 55.
3~ Alternating pressure source 54 preferably may be any standard pump capable of providing both positive pressure and negative (or vacuum) pressure, such as a piston or diaphragm pump.
=
W 096/34090 PCTrUS96/05151 Valve 52 accepts the positive pressure and negative pressure ~rom pump 54 through lines 64 and 66, respectively. Due to signals from timer 55, valve 52 causes alternating positive and negative pressure to be applied to bladder 53 from line 5 62. Valve 52 may be any type of inline valve capable of directing and regulating multiple lines. One such valve is the MAC 45S, model 45A-AA1-DAAA-lBA.
When negative pressure is applied to bladder 53, fluid will be drawn from fluid reservoir 10 until bladder 53 is 10 filled with fluid and is in a fully expanded state. During expansion of bladder 53, check valve 74 will ensure that no fluid is drawn from fluid line 58. Once the signal from timer 55 causes a positive pressure to be applied to bladder 53, the fluid contained in the bladder is forced out of the 15 bladder and through fluid line 58 to treatment chamber 46.
When fluid is forced out of bladder 53, check valve 72 will ensure that no fluid is forced back into fluid line 60. In this manner, a pulsitile, cyclic fluid flow to treatment chamber 46 is created.
Treatment chamber 46 preferably may be composed of any biocompatible, rigid material capable of being sterilized such as Teflon, polycarbonate, PVC, or stainless steel.
Treatment chamber 46 may be comprised of two sections which are secured and made leak proof through any standard means 25 such as inner and outer threads or the use of bonding agents.
In order to view vascular grafts within treatment chamber 46, a viewing port may be placed at any point on the chamber, or alternatively, the chamber may be made of an optically clear material such as polycarbonate or PVC. Inlet port 68 and 30 outlet port 70 of treatment chamber 46 allow for the perfusion and/or circulation of fluid into and through the chamber. Inlet port 68 and outlet port 70 are also used to attach treatment chamber 46 to fluid lines 58 and S6 respectively. Fluid line 56 connects chamber 46 back to 35 fluid reservoir 10 so as to create a closed system. It is to be understood that although only one treatment chamber 46 is shown in FIG. 4, fluid lines 56, 58, and 60 may be branched W096/3~090 PCTnUS96105151 so as to connect more than one treatment chamber in parallel to the system.
Treatment chamber 46 houses a porous tube 48 upon which may be placed a vascular graft scaffolding 26. Scaffolding 5 26 is discussed in detail in conjunction with FIG. 1 above.
Porous tube 48 may be comprised of any suitable rigid material, such as Teflon, PVC, polycarbonate, or stainless steel, which may be made fluid permeable. One illustrative example of a suitable porous tubing is the porous plastic 10 tubing manufactured by Porex Technologies. Alternatively, porous tube 48 may be comprised of any suitable elastomeric material, such as PET or silicone angioplasty balloons, which is capable of expanding and contracting, and which may be made fluid permeable. Treatment Chamber 46 and tube 48 may 15 both be made any length or diameter so as to hold a vascular graft scaffolding 26 of any length or diameter. This is advantageous, as the system may be used to sterilize, seed, culture, store, ship, and test vascular grafts of any size.
Porous clips or grommets 33 may be placed on tube 48 at both 20 ends of scaffolding 26 to hold the scaffolding in place on the tube during treatment.
If tube 48 is comprised of a rigid porous material, then the varying fluid pressure caused by the action of bladder pump 50 will force fluid through the porous material. The 25 fluid force through the porous material will place a varying radial stress on the vascular graft scaffolding.
Alternatively, if tube 48 is comprised of a porous elastomeric material, tube 48 may be expanded and contracted by the varying fluid pressure provided by bladder pump 50.
30 By expanding and contracting porous tube 48 with bladder pump 50, tube 48 places a varying radial stress on vascular graft ~ scaffolding 26. Moreover, as is the case with a rigid tube 48, the fluid flow through the elastomeric porous material will also place a varying radial stress on scaffolding 26.
35 In this manner, a cyclical radial loading of the scaffolding and cells supported thereon is created, resulting in vascular grafts which are formed with cells and their fibers g CA 022l9202 l997-l0-27 W 096/34090 PCTrUS96/05151 configured so as to more likely tolerate the physiological conditions found in the human body.
It is to be understood that the inlet port and outlet port of treatment chamber 14 (in FIGS. 1 and 3) and treatment 5 chamber 46 (in FIG. 4) may be sealed in a known manner (e.g., luer locks or threaded plugs) so as to create a sealed treatment chamber free from contamination. The sealed chambers may be used to sterilize, store, and ship vascular grafts or other protheses. In particular, prior to placing a 10 sealed chamber into the systems of FIGS. 1, 3, and 4, a vascular graft scaffolding 26 which is secured within the sealed chambers 14 or 46 may be sterilized by some chemical means such as ethylene oxide or peracetic acid, radiation means such as an electron beam or gamma rays, or by steam 15 sterilization. Sealed treatment chambers 14 or 46, containing the sterilized vascular graft scaffolding, may then be placed back into the systems of FIGS. 1, 3 and 4 for seeding and culturing and unsealed without contaminating the system or the vascular graft.
Seeding and culturing of the vascular graft in treatment chambers 14 and 46 is generally accomplished by known techniques, with the added benefits and advantages gained from the radial stress placed upon the vascular graft during use. Examples of suitable seeding and culturing methods for 25 the growth of three-dimensional cell cultures are disclosed in U.S. Patent No. 5,266,480, which is incorporated herein by reference. The techniques described in U.S. Patent No.
5,266,480 for establishing a three-dimensional matrix, inoculating the matrix with the desired cells, and 30 maintaining the culture may also be readily adapted by a person of ordinary skill in the art for use with the present invention.
Once the vascular graft has reached the desired level of cell density, a preservative may then be pumped into 35 treatment chambers 14 or 46. Once the treatment chambers are filled with the preservative, the inlet ports and outlet ports of the chambers may be closed, again creating a sealed W096/34090 PCT~S96105151 chamber which may then be used to store and/or ship the cultured and preserved vascular graft. Preferably, the preservative is a cryo-preservative so that the graft may be frozen in chambers 14 or 46. In this manner, sealed 5 treatment chambers 14 or 46 may be used to sterilize, culture, store, and ship vascular grafts or other protheses.
Various embodiments of the invention have been described. The descriptions are intended to be illustrative, not limitative. Thus, it will be apparent to those skilled lO in the art that modifications may be made to the invention as described without departing from the scope of the claims set out below.
Due to the inadequacies of these currently available synthetic and biological grafts, as well as the cost and CA 022l9202 l997-l0-27 PCTnUS96/05151 limited supply of homografts, tissue engineered grafts are being developed which have been sterilized and then seeded and cultured, in vitro, with cells. These tissue engineered grafts may be superior to other grafts for use in replacement 5 therapy in that they more closely display the long term dimensional stability and patency of native arteries and vessels with normal physiologic functionality.
Historically, the seeding and culturing of vascular grafts, and tissue in general, has taken place in a static 10 environment such as a Petri or culture dish. However, there are disadvantages to seeding and culturing tissue in such an environment. For example, the lack of circulation of nutrients in these static systems results in a slow and ineffective seeding and culturing process. Moreover, cells 1~ which are seeded and cultured in a dynamic environment are more likely to tolerate the physiological conditions which exist in the human body once implanted. Thus, there exists a need for a dynamic environment in which to seed and culture tissue-engineered vascular grafts and other prosthetic 20 devices.
SUk~ARY OF THE lNv~:N-lloN
It is therefore an object of the invention to provide a dynamic environment for seeding, culturing, and testing 25 vascular grafts of any desired length or diameter.
It is a further object of the invention to provide a precise mechanical device with a minimum of moving parts to provide such an environment.
It is yet a further object of the invention to provide a 30 closed system free from contamination for sterilizing, seeding, culturing, storing, shipping, and testing vascular grafts.
In accordance with the present invention, there is provided an apparatus and method for sterilizing, seeding, 35 culturing, storing, shipping, and testing vascular grafts.
Specifically, the present invention is an apparatus and method for seeding and culturing vascular grafts with human .
, PCTnUS96J051~1 WO g6~34090 cells, resulting in a tissue-engineered vascular graft populated with viable human cells.
The apparatus according to the invention comprises a fluid reservoir, a pump, at least one gra~t treatment 5 chamber, a tube for supporting the graft in the treatment chamber, and an alternating pressure source for applying a radial stress to the prosthesis housed in the treatment chamber. Applying radial stress to the vascular graft scaffold located on the tube within the treatment chamber lO during seeding and culturing results in a vascular graft with cells and their fibers oriented so as to more likely tolerate the physiological conditions found in the human body. In this manner, the invention advantageously utilizes a mechanically non-complex apparatus to create a dynamic 15 environment in which to seed and culture tissue-engineered vascular grafts or other implantable devices.
BRIEF DESCRIPTION OF THE DRAWINGS
These and other features, aspects, and advantages of the 20 present invention will become more readily apparent from the following detailed description, which should be read in conjunction with the accompanying drawings in which:
FIG. 1 is a schematic diagram illustrating an apparatus according to the present invention for sterilizing, seeding, 25 culturing, storing, shipping, and testing a prosthesis;
FIG. 2 is a block diagram illustrating a preferred embodiment of an alternating pressure source;
FIG. 3 is a schematic diagram illustrating an alternative exemplary embodiment of the present invention for 30 sterilizing, seeding, culturing, storing, shipping, and testing a prosthesis, in which a plurality of prostheses may be treated simultaneously; and FIG. 4 is a schematic diagram illustrating yet another alternative exemplary embodiment of an apparatus according to 35 the present invention for sterilizing, seeding, culturing, storing, shipping, and testing a prosthesis.
CA 02219202 1997-10-27 PCT~US96/05151 DET~TT~n DESCRIPTION OF THE lNV~N-llON
The following embodiments of the present invention will be described in the context of an apparatus and method for sterilizing, seeding, culturing, storing, shipping, and 5 testing vascular grafts, although those skilled in the art will recognize that the disclosed methods and structures are readily adaptable for broader application. Note that whenever the same reference numeral is repeated with respect to different figures, it refers to the corresponding 10 structure in each such figure.
FIG. 1 discloses a system for sterilizing, seeding, culturing, storing, shipping, and testing vascular grafts.
According to a preferred embodiment of the invention, this system primarily comprises a fluid reservoir 10, a pump 12, a 15 treatment chamber 14, and an alternating pressure source 16.
Fluid reservoir 10 is used to store fluid for the system. Two illustrative suitable reservoirs are the Gibco-BRL lL media bag and any rigid container capable of sterilization. Reservoir 10 may include a one way filter so 20 as to provide a direct source of gas to the fluid within the system. Examples of fluid which may be used in the system include, but are not limited to, sterilizing fluid, t~nn; ng fluid, fluid containing cells, or fluid containing a culture medium. It is to be understood that during testing, seeding, 25 and culturing in a preferred embodiment, the fluid may be advantageously kept at human body temperature, and may be composed of a fluid which approximates the viscosity of human blood. One illustrative example of a solution which approximates the viscosity of blood is saline with glycerol.
The fluid contained in reservoir 10 is retrieved through fluid line 18 by pump 12. Fluid line 18, as well as all other fluid lines in the system, may be made of any type of medical grade, durable tubing suitable for transporting the fluid in use. Pump 12 may be preferably any fluid pump which 35 can achieve variable ~low rates. One such pump is the Masterflex L/S Digital Drive peristaltic pump manufactured by Cole-Palmer, although one skilled in the art could select PC~nUS961~5~5 WO 96/340gO
from a variety of commercially available pumps. Pump 12 propels the fluid from reservoir 10 to treatment chamber 14 through fluid line 20.
Treatment chamber 14 preferably may be composed of any 5 biocompatible, rigid material capable of being sterilized such as Teflon, polycarbonate, PVC, or stainless steel.
Treatment chamber 14 may be comprised of two sections which are secured and made leak proof through any standard means such as inner and ou~er threads or the use of bonding agents.
10 In order to view vascular grafts within treatment chamber 14, a viewing port may be placed at any point on the chamber, or alternatively, the chamber may be made of an optically clear material such as polycarbonate or PVC. Inlet port 28 and outlet port 30 of ~reatment chamber 14 allow for the 1~ perfusion and/or circulation of fluid into and through the chamber. Inlet port 28 and outlet port 30 are also used to attach treatment chamber 14 to fluid lines 20 and 22 respectively. Fluid line 22 connects chamber 14 back to fluid reservoir 10 so as to create a closed system.
Treatment chamber 14 houses an expandable tube 32 upon which may be placed a vascular graft scaffolding 26. As is discussed in detail in both the patents incorporated by reference below, scaffolding 26 may illustratively consist of any knitted, braided, woven, felted, or synthesized materials 2~ that are bioresorbable and/or biocompatible, as well as any native graft scaffolding material. Tube 32 may be comprised of any suitable elastomeric material, such as PET or silicone angioplasty balloons, which is capable of expanding and contracting. Treatment Chamber 14 and tube 32 may be made 30 any length or diameter so as to hold a vascular graft scaffolding 26 of any length or diameter. This is advantageous, as the system may be used to sterilize, seed, culture, store, ship, and test vascular grafts of any size, ~uch as coronary, carotid, iliac, and peripheral leg grafts.
35 A porous clip or grommet 33 may be placed on tube 32 at both ends of scaffolding 26 to hold the scaffolding firmly in = place on the tube during treatment. However, one skilled in 096/34090 PCTrUS96/05151 the art will understand that any structure which allows for retention of the scaffolding 26 on tube 32 may be used.
Grommets 33 are beneficial, as the tubing can be made smaller than the grafts so as to allow for the perfusion and/or circulation of fluids in between the graft and the tube, without the possibility of slippage of the graft on the tube.
Tube 32 may be expanded and contracted by alternating pressure source 16, a preferred embodiment of which is shown in detail in FIG. 2. Specifically, FIG. 2 shows a pump 34 which may be any standard pump capable of providing both positive pressure and negative (or vacuum) pressure, such as a piston or diaphragm pump. Valve 36 accepts the positive pressure and negative pressure from pump 34 through lines 40 and 42 respectively. Due to signal& from timer 38, valve 36 causes alternating pressure to be applied to tube 32 from line 24. Valve 36 may be any type of inline valve capable of directing and regulating multiple pressure lines. One such valve is the MAC 45S, model 45A-AA1-DAAA-lBA.
By expanding and contracting tube 32 with alternating pressure source 16, tube 32 places a varying radial stress on vascular graft scaffolding 26. This radial stress is advantageous as it can be detected by living cells attached to the scaffolding, thus causing the cells to align themselves parallel to the axis of stress and to secrete extracellular matrix molecules which are also aligned parallel to the axis of stress. In this manner, vascular grafts are formed with cells and their fibers configured so as to more likely tolerate the physiological conditions found in the human body.
The system according to the present invention may contain a plurality of chambers 14 for treating a plurality of vascular grafts. FIG. 3 discloses a system according to the present invention which contains two treatment chambers 14. Although FIG. 3 illustrates the connection of only two treatment chambers to the system, it will be apparent to one skilled in the art that any number of chambers may be connected to the system in similar fashion. Specifically, WO 96/34090 PCTnUS96105151 line 20 may be split to connect to each inlet 28, line 24 may be split to connect to each tube 32, and line 22 may be split to connect to each outlet 30 of each chamber 14 in the system. In this manner, a plurality of vascular grafts may 5 be simultaneously seeded, cultured, or tested.
Alternatively, each treatment chamber 14 may be connected to a separate reservoir 10 and pump 12 so that multiple treatment chambers in a system would only share a single alternating pressure source 16. It is to be 10 understood that a pump 12 with multiple pump lines may also be used so that each treatment chamber 14 in the system would use the same alternating pressure source and same pump 12 (each using a different pump line), but would be connected to a different media reservoir 10.
FIG. 4 discloses an alternative embodiment of the invention for sterilizing, seeding, culturing, storing, shipping, and testing vascular grafts. According to this - embodiment of the invention, the system primarily comprises a fluid reservoir 10, a bladder pump S0, a treatment chamber 20 46, and an alternating pressure source 54.
Fluid reservoir 10 and the fluids which it may contain are described in detail in conjunction with FIG. 1. The fluid contained in reservoir 10 is retrieved through fluid line 60 by bladder pump 50. Fluid line 60, as well as all 25 other fluid lines in the system, may be made of any type of medical grade, durable tubing suitable for transporting the fluid in use. Bladder pump 50 is comprised of a pneumatic pressure chamber 51 and a bladder 53, which may be comprised of an suitable elastomeric material. An illustrative 30 suitable bladder is the Cutter/Miles double valved hand activated blood pump. Bladder pump 50 forces fluid from reservoir 10 to treatment chamber 46 through fluid line 58 by being alternately compressed and expanded by alternating - pressure source 54 in conjunction with valve 52 and timer 55.
3~ Alternating pressure source 54 preferably may be any standard pump capable of providing both positive pressure and negative (or vacuum) pressure, such as a piston or diaphragm pump.
=
W 096/34090 PCTrUS96/05151 Valve 52 accepts the positive pressure and negative pressure ~rom pump 54 through lines 64 and 66, respectively. Due to signals from timer 55, valve 52 causes alternating positive and negative pressure to be applied to bladder 53 from line 5 62. Valve 52 may be any type of inline valve capable of directing and regulating multiple lines. One such valve is the MAC 45S, model 45A-AA1-DAAA-lBA.
When negative pressure is applied to bladder 53, fluid will be drawn from fluid reservoir 10 until bladder 53 is 10 filled with fluid and is in a fully expanded state. During expansion of bladder 53, check valve 74 will ensure that no fluid is drawn from fluid line 58. Once the signal from timer 55 causes a positive pressure to be applied to bladder 53, the fluid contained in the bladder is forced out of the 15 bladder and through fluid line 58 to treatment chamber 46.
When fluid is forced out of bladder 53, check valve 72 will ensure that no fluid is forced back into fluid line 60. In this manner, a pulsitile, cyclic fluid flow to treatment chamber 46 is created.
Treatment chamber 46 preferably may be composed of any biocompatible, rigid material capable of being sterilized such as Teflon, polycarbonate, PVC, or stainless steel.
Treatment chamber 46 may be comprised of two sections which are secured and made leak proof through any standard means 25 such as inner and outer threads or the use of bonding agents.
In order to view vascular grafts within treatment chamber 46, a viewing port may be placed at any point on the chamber, or alternatively, the chamber may be made of an optically clear material such as polycarbonate or PVC. Inlet port 68 and 30 outlet port 70 of treatment chamber 46 allow for the perfusion and/or circulation of fluid into and through the chamber. Inlet port 68 and outlet port 70 are also used to attach treatment chamber 46 to fluid lines 58 and S6 respectively. Fluid line 56 connects chamber 46 back to 35 fluid reservoir 10 so as to create a closed system. It is to be understood that although only one treatment chamber 46 is shown in FIG. 4, fluid lines 56, 58, and 60 may be branched W096/3~090 PCTnUS96105151 so as to connect more than one treatment chamber in parallel to the system.
Treatment chamber 46 houses a porous tube 48 upon which may be placed a vascular graft scaffolding 26. Scaffolding 5 26 is discussed in detail in conjunction with FIG. 1 above.
Porous tube 48 may be comprised of any suitable rigid material, such as Teflon, PVC, polycarbonate, or stainless steel, which may be made fluid permeable. One illustrative example of a suitable porous tubing is the porous plastic 10 tubing manufactured by Porex Technologies. Alternatively, porous tube 48 may be comprised of any suitable elastomeric material, such as PET or silicone angioplasty balloons, which is capable of expanding and contracting, and which may be made fluid permeable. Treatment Chamber 46 and tube 48 may 15 both be made any length or diameter so as to hold a vascular graft scaffolding 26 of any length or diameter. This is advantageous, as the system may be used to sterilize, seed, culture, store, ship, and test vascular grafts of any size.
Porous clips or grommets 33 may be placed on tube 48 at both 20 ends of scaffolding 26 to hold the scaffolding in place on the tube during treatment.
If tube 48 is comprised of a rigid porous material, then the varying fluid pressure caused by the action of bladder pump 50 will force fluid through the porous material. The 25 fluid force through the porous material will place a varying radial stress on the vascular graft scaffolding.
Alternatively, if tube 48 is comprised of a porous elastomeric material, tube 48 may be expanded and contracted by the varying fluid pressure provided by bladder pump 50.
30 By expanding and contracting porous tube 48 with bladder pump 50, tube 48 places a varying radial stress on vascular graft ~ scaffolding 26. Moreover, as is the case with a rigid tube 48, the fluid flow through the elastomeric porous material will also place a varying radial stress on scaffolding 26.
35 In this manner, a cyclical radial loading of the scaffolding and cells supported thereon is created, resulting in vascular grafts which are formed with cells and their fibers g CA 022l9202 l997-l0-27 W 096/34090 PCTrUS96/05151 configured so as to more likely tolerate the physiological conditions found in the human body.
It is to be understood that the inlet port and outlet port of treatment chamber 14 (in FIGS. 1 and 3) and treatment 5 chamber 46 (in FIG. 4) may be sealed in a known manner (e.g., luer locks or threaded plugs) so as to create a sealed treatment chamber free from contamination. The sealed chambers may be used to sterilize, store, and ship vascular grafts or other protheses. In particular, prior to placing a 10 sealed chamber into the systems of FIGS. 1, 3, and 4, a vascular graft scaffolding 26 which is secured within the sealed chambers 14 or 46 may be sterilized by some chemical means such as ethylene oxide or peracetic acid, radiation means such as an electron beam or gamma rays, or by steam 15 sterilization. Sealed treatment chambers 14 or 46, containing the sterilized vascular graft scaffolding, may then be placed back into the systems of FIGS. 1, 3 and 4 for seeding and culturing and unsealed without contaminating the system or the vascular graft.
Seeding and culturing of the vascular graft in treatment chambers 14 and 46 is generally accomplished by known techniques, with the added benefits and advantages gained from the radial stress placed upon the vascular graft during use. Examples of suitable seeding and culturing methods for 25 the growth of three-dimensional cell cultures are disclosed in U.S. Patent No. 5,266,480, which is incorporated herein by reference. The techniques described in U.S. Patent No.
5,266,480 for establishing a three-dimensional matrix, inoculating the matrix with the desired cells, and 30 maintaining the culture may also be readily adapted by a person of ordinary skill in the art for use with the present invention.
Once the vascular graft has reached the desired level of cell density, a preservative may then be pumped into 35 treatment chambers 14 or 46. Once the treatment chambers are filled with the preservative, the inlet ports and outlet ports of the chambers may be closed, again creating a sealed W096/34090 PCT~S96105151 chamber which may then be used to store and/or ship the cultured and preserved vascular graft. Preferably, the preservative is a cryo-preservative so that the graft may be frozen in chambers 14 or 46. In this manner, sealed 5 treatment chambers 14 or 46 may be used to sterilize, culture, store, and ship vascular grafts or other protheses.
Various embodiments of the invention have been described. The descriptions are intended to be illustrative, not limitative. Thus, it will be apparent to those skilled lO in the art that modifications may be made to the invention as described without departing from the scope of the claims set out below.
Claims (23)
1. An apparatus, comprising:
a housing defining a seeding and culturing chamber having a first port and a second port for flow of fluid therethrough;
a support structure located within said chamber configured and dimensioned to support a tubular prosthesis;
and means for imparting a radial stress to the prosthesis.
a housing defining a seeding and culturing chamber having a first port and a second port for flow of fluid therethrough;
a support structure located within said chamber configured and dimensioned to support a tubular prosthesis;
and means for imparting a radial stress to the prosthesis.
2. The apparatus of claim 1 wherein said support structure is moveable between a first position and a second position.
3. The apparatus of claim 2 wherein said imparting means comprises means for moving said support structure between the first and second positions.
4. The apparatus of claim 3, wherein said support structure comprises an expandable tubular member having an outer diameter that is variable in response to pressure within the tubular member, said tubular member adapted to receive the tubular member, said tubular member adapted to receive the tubular prosthesis thereover.
5. The apparatus of claim 4, wherein said moving means comprises an alternating pressure source communication with the tubular member for moving said support structure from the first position to the second position.
6. The apparatus of any one of claims 1-5, wherein said support structure is comprises of a rigid or elastic material which may be porous.
7. The apparatus of claim 6, wherein said imparting means comprises means for forcing fluid flow through said support structure.
8. The apparatus of claim 7, wherein said forcing means comprises a pump providing alternating pressure.
9. The apparatus of claim 4, wherein the expandable tubular member comprises an angioplasty balloon.
10. The apparatus of claim 5, wherein said alternating pressure source comprises:
a pump for providing a first level of pressure and second level pressure;
a valve connected in between said pump and said support structure for alternatingly allowing the first level of pressure and the second level of pressure to be placed on said support structure, wherein the first level of pressure corresponds to the first position and the second level of pressure corresponds to the second position.
a pump for providing a first level of pressure and second level pressure;
a valve connected in between said pump and said support structure for alternatingly allowing the first level of pressure and the second level of pressure to be placed on said support structure, wherein the first level of pressure corresponds to the first position and the second level of pressure corresponds to the second position.
11. The apparatus of claim 10, wherein the valve is connected to a timer for variably opening and closing the valve.
12. The apparatus of claim 4, wherein the expandable tubular member is sized such that in at least the first position the tubular member and prosthesis are spaced apart to define a passage that permits fluid to circulate between said tubular member and said prosthesis.
13. The apparatus of any one of claims 1-12, wherein said prosthesis is held in place on said support structure by a grommet.
14. The apparatus of claim 1, further comprising a plurality of said housings.
15. The apparatus of claim 1, wherein said housing comprises a first and second ports which may be sealed for enclosing, sterilizing, storing, and shipping the vascular graft.
16. The apparatus of claim 8, wherein said pump is a bladder pump.
17. A method for seeding and culturing a prosthesis, comprising:
exposing the prosthesis to a fluid media for seeding and culturing; and imparting a radial stress to the prosthesis during said seeding and culturing to encourage a desired alignment of cells on the prosthesis.
exposing the prosthesis to a fluid media for seeding and culturing; and imparting a radial stress to the prosthesis during said seeding and culturing to encourage a desired alignment of cells on the prosthesis.
18. The method of claim 17, wherein said step of imparting radial stress comprises:
placing said prosthesis on a support structure; and moving said support structure between a first position and a second position so that the radial stress is imparted to the prosthesis.
placing said prosthesis on a support structure; and moving said support structure between a first position and a second position so that the radial stress is imparted to the prosthesis.
19. The method of claim 18, wherein said support structure comprises a rigid or elastic tube.
20. The method of claim 19, which comprises moving said tube from the first to the second position by a pump, said pump alternatingly providing a first level and a second level of pressure.
21. The method of claim 17, wherein said step of imparting radial stress comprises:
placing said prosthesis on a porous support structure; and forcing the fluid media through the porous support structure so that radial stress is imparted to the prosthesis from the fluid media.
placing said prosthesis on a porous support structure; and forcing the fluid media through the porous support structure so that radial stress is imparted to the prosthesis from the fluid media.
22. The method of claim 21, wherein the porous support structure comprises a rigid tubular member.
23. The method of claim 17, wherein said prosthesis is tubular and its diameter is varied by said step of variably moving said prosthesis.
Applications Claiming Priority (2)
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US43076895A | 1995-04-27 | 1995-04-27 | |
US430,768 | 1995-04-27 |
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CA2219202A1 true CA2219202A1 (en) | 1996-10-31 |
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CA002219202A Abandoned CA2219202A1 (en) | 1995-04-27 | 1996-04-09 | Apparatus and method for sterilizing, seeding, culturing, storing, shipping and testing tissue, synthetic or native vascular grafts |
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EP (1) | EP0822978A4 (en) |
JP (1) | JP4059301B2 (en) |
KR (1) | KR19990008070A (en) |
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CA (1) | CA2219202A1 (en) |
NZ (1) | NZ306304A (en) |
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Cited By (1)
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CN109804059A (en) * | 2016-08-03 | 2019-05-24 | 诺斯威克公园医学研究所有限公司 | Bioreactor and the method for handling biomaterial |
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EP2075015B1 (en) * | 1997-07-03 | 2015-03-11 | Massachusetts Institute of Technology | Tissue-engineered constructs |
US6066495A (en) * | 1998-03-05 | 2000-05-23 | Tissue Engineering, Inc. | Methods and apparatus for the conditioning of ligament replacement tissue |
AU2002230396B2 (en) * | 2000-10-06 | 2012-06-07 | Krstec, Victor | System and method to simulate hemodynamics |
EP1205541A1 (en) * | 2000-11-14 | 2002-05-15 | Klaus Dr. Giehl | Procedure for the long-term cultivation of organo-typic slices of brain and other postnatal tissues, in particular of adult mammals |
JP2002315566A (en) | 2001-04-24 | 2002-10-29 | Takagi Ind Co Ltd | Cell and tissue-culturing apparatus |
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JP4061149B2 (en) * | 2002-07-24 | 2008-03-12 | 株式会社ティッシュエンジニアリングイニシアティブ | Cell culture device and cell culture method |
JP2006223317A (en) * | 2003-05-15 | 2006-08-31 | Univ Waseda | Method of cell seeding |
JP2006223101A (en) * | 2003-05-15 | 2006-08-31 | Univ Waseda | Living organism tissue retaining unit and living organism tissue treating apparatus including the same |
GB0410177D0 (en) * | 2004-05-07 | 2004-06-09 | Univ Wales Medicine | Engineered tubular tissue structures |
DE102005049905A1 (en) * | 2005-10-17 | 2007-04-19 | Medizinische Hochschule Hannover | Method and device for producing a joint replacement |
JP4981374B2 (en) | 2006-07-10 | 2012-07-18 | パーパス株式会社 | Cell or tissue culture apparatus and culture method |
JP5433129B2 (en) | 2006-07-10 | 2014-03-05 | パーパス株式会社 | Cell or tissue culture method |
EP2049159A4 (en) * | 2006-08-11 | 2011-08-17 | Univ Queensland | Scaffold treatment - device and method |
US8058057B2 (en) * | 2008-05-30 | 2011-11-15 | Corning Incorporated | Cell culture apparatus and method |
US9090863B2 (en) | 2010-05-17 | 2015-07-28 | Pall Corporation | System for seeding cells onto three dimensional scaffolds |
WO2011146046A1 (en) * | 2010-05-17 | 2011-11-24 | Yale University | System for seeding cells onto three dimensional scaffolds |
CN105296433B (en) | 2014-08-01 | 2018-02-09 | 中山康方生物医药有限公司 | A kind of CTLA4 antibody, its medical composition and its use |
EP3460040A4 (en) | 2016-05-19 | 2020-01-15 | Koji Saito | Culture device, culture method and cultured organ produced by culture method |
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- 1996-04-09 CA CA002219202A patent/CA2219202A1/en not_active Abandoned
- 1996-04-09 NZ NZ306304A patent/NZ306304A/en unknown
- 1996-04-09 AU AU54843/96A patent/AU703117B2/en not_active Ceased
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- 1996-04-09 KR KR1019970707594A patent/KR19990008070A/en not_active Application Discontinuation
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CN109804059A (en) * | 2016-08-03 | 2019-05-24 | 诺斯威克公园医学研究所有限公司 | Bioreactor and the method for handling biomaterial |
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KR19990008070A (en) | 1999-01-25 |
AU5484396A (en) | 1996-11-18 |
NZ306304A (en) | 1999-03-29 |
AU703117B2 (en) | 1999-03-18 |
JP4059301B2 (en) | 2008-03-12 |
WO1996034090A1 (en) | 1996-10-31 |
JPH11504216A (en) | 1999-04-20 |
EP0822978A1 (en) | 1998-02-11 |
EP0822978A4 (en) | 1999-08-18 |
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